The present invention relates to the method and apparatus of PCT Application No. PCT/IL97/00249, International Publication No. WO 98/04182, published 5 Feb. 1998, and PCT Application No. PCT/IL00/00307, International Publication No. WO 00/74551, published 14 Dec. 2000, which applications are hereby incorporated by reference as if fully set forth herein.
The above PCT applications relate to the non-invasive detection and monitoring of various physiological states or medical conditions of a patient by using a digit-probe for monitoring the peripheral arterial tone (PAT) of the patient. The present invention relates to non-invasively evaluating endothelial activity in a patient, particularly for indicating the presence of an endothelial dysfunction condition, preferably by using the digit-probe of those applications.
The active control of vascular smooth muscle (VSM) tone in the arteries of the finger (or toe) is by way of alpha-adrenergic sympathetic nervous control. Certain locally occurring autoregulatory mechanisms may also be important in local vascular homeostasis; for example, an intrinsic contractile response to being stretched tends to constrict vessels which are distended due to increased transmural pressure (myogenic theory of autoregulation). Other examples of local autoregulation include the vasodilatory response to the presence of high concentrations of metabolic metabolites in active tissues, and the veno-arteriolar vasoconstrictory response to venous distention. Certain special design features of the peripheral arterial tone (PAT) probe described in the above-cited patent applications were specifically addressed to controlling the influence of the above-mentioned veno-arteriolar and myogenic influences.
In addition to intrinsic autoregulatory control and neurogenically mediated electromechanical coupling of vascular smooth muscle, various pharmacological agents can also affect the VSM contractile state, without actually altering the VSM resting membrane potential, through a process called pharmacomechanical coupling. Circulating vasoactive factors derived outside the blood vessel wall include catecholamines from nerve endings serving VSM such as norepinephrine, or circulating factors such as vasopressin and epinephrine, and factors derived from circulating elements such as serotonin from circulating platelets.
A further mechanism which is known to affect the contractile state of VSM is that of the functioning of the single celled surface lining of the inside walls of the blood vessels known as the endothelium. The endothelium has been found to produce a number of vasoactive substances which are very important in vascular homeostasis These factors can produce either an increase in the level of tonic activity of the blood vessels' VSM (vasoconstriction), or a decrease in the level of VSM tonic activity (vasodilation).
One such factor is an endothelial derived relaxing factor, which may produce vasodilatation by hyperpolarizing the VSM membrane, thereby raising the threshold for electromechanically mediated contraction. Under such conditions, a given level of sympathetic neural activation could result in a lesser degree of vasoconstriction, that is, relative vasodilation.
The term “endothelial dysfunction”, or ED, refers to an impairment of the ability of the endothelial cell layer to produce an appropriate vasodilatory response. An example of this is the vasodilatory response of coronary arteries to acetylcholine (Ach), occurring in healthy vessels, as opposed to a paradoxical vasoconstrictory response to Ach in vessels with ED: Ludmer P L, Selwyn A P, Shook T L, et al., “Paradoxical Vasoconstriction Induced by Acetylcholine in Atherosclerotic Coronary Arteries”, N. Engl. J. Med. 315:1046 (1986). Another example of endothelium mediated vasodilation, which is important in regulating vascular tone, is the vasodilatory response mediated by endothelium in response to increases in shear stress due to increased blood flow velocity within arteries: Kuo L, Davis M J, Chilian W M, “Endothelium-Dependent Flow Induced Dilation of Isolated Coronary Arterioles”, Am J Physiol 259; H1063 (1990). This mechanism can, for example, modulate neurogenically induced vasoconstriction to better achieve homeostatic function.
The early identification of ED could therefore be of considerable clinical importance since it could provide a way of identifying patients who could benefit from therapeutic intervention at an early pre-clinical stage of the condition. It is now accepted that impaired peripheral endothelial function is an independent predictor of long term cardiac events.
No currently available test of endothelial function is suitable for wide clinical application for determining the presence of ED, which is now well accepted as an important factor in the pathogenesis of atherosclerotic cardiovascular disease. The tests currently available are either highly invasive (i.e., measuring the hemodynamic changes caused by intracoronary instillation of vasoactive drugs), or require the use of technically difficult vascular imaging studies, expensive apparatus, and highly skilled staff. As an example, one current diagnostic method for detecting ED is known as the Brachial Artery Duplex (BAD) Test. This test involves inflating a blood pressure cuff above the patient's elbow to a predetermined occluding pressure (e.g., 300 mm Hg) so as to stop arterial blood flow to the arm below the cuff for a predetermined period of time (e.g., 5 minutes). A Doppler flow rate probe and an echo Doppler are used to measure relative changes in flow velocity and brachial artery caliber, respectively, before, during, and after the application of the occluding pressure. The results following the release of the pressure cuff are compared to the pre-occlusion state. If there is a sufficient increase in flow velocity and artery caliber, the patient is considered to have normal endothelial function.
The above-described diagnostic method has several disadvantages. For example, it requires expensive apparatus and specialized personnel, and it suffers from a lack of accuracy and poor inter and intra-observer reproducibility. The method is also very uncomfortable to the subject since the pressure cuff is very tight around the subject's arm and blood flow must be stopped for a relatively long time, e.g., 5 minutes.
The above-cited PCT Application PCT/IL00/00307 briefly described the manner in which the PAT digit-probe method could be used in assessing endothelial responsiveness and in diagnosing ED. Two basic findings vere described;
(A). One finding briefly described was the association between exercise induced PAT signal attenuation and the presence of endothelial dysfunction, and the lack of such exercise induced attenuation in patients considered to have normal endothelial function. This showed that the PAT response to exercise could be used to help distinguish between the presence or absence of endothelial dysfunction. An additional way in which the PAT response to exercise stress can be used to distinguish between normal and abnormal endothelial functioning is by examining the changes in the PAT signal during the post exercise recovery period. While the presence of a sub-threshold attenuation level could be indicative of endothelial dysfunction, a sufficiently great post exercise increase in the PAT signal amplitude could alter the diagnosis.
(B). Also briefly described was the existence of a significant linear correlation between the outcome of the established BAD (brachial artery duplex) Test and the concurrent measurement of the PAT response to the same eliciting stressor (i.e., fore-arm blood flow occlusion) used in that test. The brachial artery response is most commonly expressed in terms of the percentage change in brachial artery diameter, referred to as flow mediated dilation or % FMD. The PAT correlate of this brachial artery response is the ratio of pulsewave amplitudes after and before the arterial occlusion.
The present application presents a number of new findings, which can substantially improve the performance of the PAT probe in evaluating endothelial function and diagnosing the presence of endothelial dysfunction (ED).